Goldpaul6180

Autopsy validation is still required for a definitive diagnosis of Parkinson's disease (Postuma et al., 2015), where the presence of Lewy bodies and Lewy neurites, composed primarily of alpha-synuclein, are observed in stereotyped patterns throughout regions of the brainstem, limbic, and neocortical regions of the brain (Braak et al., 2003). In spite of these relatively reliable observed patterns of alpha-synuclein pathology, there is a large degree of heterogeneity in the timing and features of neuropsychiatric and cognitive dysfunction in Parkinson's disease (Fereshtehnejad et al., 2015; Selikhova et al., 2009; Williams-Gray et al., 2013). Detailed studies of their neuropathological substrates of cognitive dysfunction and their associations with a variety of in vivo biomarkers have begun to disentangle this complex relationship, but ongoing multicentered, longitudinal studies of well-characterized and autopsy validated cases are still required.Communication difficulties are a ubiquitous symptom of Parkinson's disease and include changes to both motor speech and language systems. Communication challenges are a significant driver of lower quality of life. They are associated with decreased communication participation, social withdrawal, and increased risks for social isolation and stigmatization in persons with Parkinson's disease. Recent theoretical advances and experimental evidence underscore the intersection of cognition and motor processes in speech production and their impact on spoken language. This chapter overviews a growing evidence base demonstrating that cognitive impairments interact with motor changes in Parkinson's disease to negatively affect communication abilities in myriad ways, at all stages of the disease, both in the absence and presence of dementia. The chapter highlights common PD interventions (pharmacological, surgical, and non-pharmacological) and how cognitive influences on speech production outcomes are considered in each.Cognitive control is the ability to act according to plan. Problems with cognitive control are a primary symptom and a major decrement of quality of life in Parkinson's disease (PD). Individuals with PD have problems with seemingly different controlled processes (e.g., task switching, impulsivity, gait disturbance, apathetic motivation). We review how these varied processes all rely upon disease-related alteration of common neural substrates, particularly due to dopaminergic imbalance. A comprehensive understanding of the neural systems underlying cognitive control will hopefully lead to more concise and reliable explanations of distributed deficits. However, high levels of clinical heterogeneity and medication-invariant control deficiencies suggest the need for increasingly detailed elaboration of the neural systems underlying control in PD.While motor symptoms are the most recognized features of Parkinson's disease (PD), cognitive dysfunction is a key determinant of consequences of PD in real-life. In this chapter we review important domains where cognitive dysfunction negatively impacts the lives of people with PD (PwPD), such as difficulties in occupational and social life, and instrumental ADLs such as driving. Early loss of employment has important effects for PwPD, their families, and society. PwPD experience higher rates of family and social discord as well as important changes in their social roles. These processes are largely mediated through cognitive dysfunction, particularly difficulties processing and understanding emotions, decreased attention, and executive dysfunction. Cognitive dysfunction is also an important mediator of driving impairments, which contributes to decreased independence in PwPD. Finally, we briefly review the costs associated with cognitive impairment in PD. CathepsinGInhibitorI Both indirect and direct costs for PwPD with cognitive impairment are substantially higher than for PwPD with normal cognition.

Gefapixant is an oral P2X

receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough.

COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (111), using a computer-generated allocation schedule, to one of three treatment groups placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given oran acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough.

Merck Sharp & Dohme.

Merck Sharp & Dohme.This Review describes current knowledge on the epidemiology and causes of child and adolescent obesity, considerations for assessment, and current management approaches. Before the COVID-19 pandemic, obesity prevalence in children and adolescents had plateaued in many high-income countries despite levels of severe obesity having increased. However, in low-income and middle-income countries, obesity prevalence had risen. During the pandemic, weight gain among children and adolescents has increased in several jurisdictions. Obesity is associated with cardiometabolic and psychosocial comorbidity as well as premature adult mortality. The development and perpetuation of obesity is largely explained by a bio-socioecological framework, whereby biological predisposition, socioeconomic, and environmental factors interact together to promote deposition and proliferation of adipose tissue. First-line treatment approaches include family-based behavioural obesity interventions addressing diet, physical activity, sedentary behaviours, and sleep quality, underpinned by behaviour change strategies. Evidence for intensive dietary approaches, pharmacotherapy, and metabolic and bariatric surgery as supplemental therapies are emerging; however, access to these therapies is scarce in most jurisdictions. Research is still needed to inform the personalisation of treatment approaches of obesity in children and adolescents and their translation to clinical practice.

The accumulation of disparate diseases in complex multimorbidity makes prevention difficult if each disease is targeted separately. We aimed to examine obesity as a shared risk factor for common diseases, determine associations between obesity-related diseases, and examine the role of obesity in the development of complex multimorbidity (four or more comorbid diseases).

We did an observational study and used pooled prospective data from two Finnish cohort studies (the Health and Social Support Study and the Finnish Public Sector Study) comprising 114 657 adults aged 16-78 years at study entry (1998-2013). A cohort of 499 357 adults (aged 38-73 years at study entry; 2006-10) from the UK Biobank provided replication in an independent population. BMI and clinical characteristics were assessed at baseline. BMIs were categorised as obesity (≥30·0 kg/m

), overweight (25·0-29·9 kg/m

), healthy weight (18·5-24·9 kg/m

), and underweight (<18·5 kg/m

). Via linkage to national health records, participants werd by age 55 years in participants with obesity, and degree of obesity was associated with complex multimorbidity in a dose-response relationship. Compared with obesity, the association between overweight and complex multimorbidity was more modest (HR 2·67, 95% CI 1·94-3·68; PAF 13·3% [95% CI 9·6-16·3]). The same pattern of results was observed in the UK Biobank cohort.

Obesity is associated with diverse, increasing disease burdens, and might represent an important target for multimorbidity prevention that avoids the complexities of multitarget preventive regimens.

Wellcome Trust, Medical Research Council, National Institute on Aging.

Wellcome Trust, Medical Research Council, National Institute on Aging.Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed tuberculosis and it caused 1·5 million deaths. Around a quarter of deaths caused by antimicrobial resistance are due to rifampicin-resistant tuberculosis. Antimicrobial resistance surveillance systems for many bacterial pathogens are still in the early stages of implementation in many countries, and do not yet allow for the estimation of disease burden at the national level. In this Personal View, we present the achievements, challenges, and way forward for the oldest and largest global antimicrobial resistance surveillance system. Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug Resistance Surveillance has served as a platform for the evaluation of the trends in anti-tuberculosis drug resistance for over 25 years at country, regional, and global levels. With an estimated 465 000 incident cases of multidrug-resistant and rifampicin-resistant tuberculosis in 2019, drug-resistant tuberculosis remains a public health crisis. The COVID-19 pandemic has reversed years of progress in providing essential tuberculosis services and reducing disease burden. The number of people diagnosed with drug-resistant tuberculosis has dropped by 22% since before the pandemic, and the number of patients provided with treatment for drug-resistant tuberculosis has dropped by 15%. Now more than ever, closing gaps in the detection of drug-resistant tuberculosis requires investment in research and development of new diagnostic tools and their rollout, expansion of sample transport systems, and the implementation of data connectivity solutions.According to the latest reports from WHO, the incidence of antibiotic-resistant bacterial infections is increasing worldwide, resulting in increased morbidity and mortality and a rising pressure on health-care systems. However, the development of new antibiotics is an expensive and time-consuming process, urging scientists to seek alternative antimicrobial strategies. Over the past few decades, the concept of therapeutic administration of bacteriophages (also known as phages) has gained popularity worldwide. Although conceptually promising, the widespread implementation of phage therapy in routine clinical practice is restricted by the scarcity of safety and efficacy data obtained according to the strict standards of the applicable clinical trial regulations. In this systematic review, we list clinical data published between Jan 1, 2000 and Aug 14, 2021 on the safety and efficacy of phage therapy for difficult-to-treat bacterial infections, and provide an overview of trials and case studies on the use of phage therapy in several medical disciplines.Parvovirus B19 infection in pregnancy may have a poor outcome for the fetus. Ocular anomalies, brain damage with hydrocephalus and central nervous system (CNS) scarring, cleft lip and hypospadias, as well myocarditis and congenital heart disease have been reported. We present a case of a preterm female neonate born with ascites, hydrothorax and congenital diaphragmatic eventration (CDE), with a prenatal diagnosis of congenital diaphragmatic hernia (CDH). The neonate was born prematurely at 32 weeks gestation with caesarean section due to a previous caesarean delivery. She was immediately intubated in the delivery room, transferred in the Neonatal Intensive Care Unit (NICU) and supported with high frequency oscillatory ventilation (HFOV). The diagnosis of CDH was sonographically estimated from the 20th week of gestation and surgical correction was decided. During surgery CDE was diagnosed instead of CDH and despite postoperatively care the neonate developed disseminated intravascular coagulation and finally died in the 40th hour of life.